JPH04502165A - chiral sultam - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] chiral sultam The present invention provides single enantiomers of a given chiral sultam in substantially optically pure form. This invention relates to a composition comprising thioma. The invention also provides a method for preparing this type of composition, and and a chiral auxiliary of this type of chiral sultam, i.e., a chiral template (on which (a) capable of carrying out body-selective chemical reactions.

J. Oro. Chem. 48 537-542 (1983) 4: 3-chloro-1,2-penzisothiazole using sodium borohydride 1. By reducing 1-dioxide, the following formula: (where B is CHs, C4H9 , i-C3H7 and cyclobentyl) with 3-monosubstituted 1.2 - The preparation of a racemic mixture of penzisothiazine 1,1-dioxide has been disclosed. It is shown. No uses have been disclosed for this type of compound, especially for racemic mixtures. There was apparently no attempt to separate the molecule into its constituent enantiomers. J. Chei. Sac Perkin 1 2589-2594 (197 4) D is a certain type of 3,3-di-substituted-1,2-penziisothiazine-1,1-di Although oxides are disclosed, these compounds do not have any chiral properties. A similar compound was disclosed in J Chem, Soc 1339 (1952). has been done.

Chiral 3-monosubstituted-1,2-benzisothiazine 1゜1-dioxide (hereinafter referred to as Preparation of subchiral sultams) as single enantiomers with high optical purity We have now developed a method that makes this possible. The results of studying the chemistry of single enantiomers As a result, they act as effective chiral auxiliaries for a range of prochiral reactants. This allows stereoselective chemical reactions to be performed on a range of chiral and non-chiral reagents. We found that this can be done on prochiral reactants using drugs. This conclusion As a result, this type of compound is highly stereospecific at specific positions during the synthesis of a given molecule. Extremely useful in the pharmaceutical and agrochemical industries where complex chemical reactions often need to be carried out. It became useful.

According to the invention, the following general formula: (wherein the R groups are independently hydrogen or C8-C6 alkyl, and the R] groups are C3-C 2° alkyl or aryl substituted alkyl in substantially optically pure form A single enantiomer of a chiral sultam is provided which has the following configuration.

The term substantially optically pure refers to a given enantiomer of a chiral sultam. of the total weight of the sample in question, preferably at least It is intended to consist of 90%.

The R group is preferably selected from hydrogen, methyl, ethyl or propyl. (a) All R groups are hydrogen, or (b) any three R groups are hydrogen. and the fourth one is methyl or ethyl. Ru.

The R1 group is suitably an alkyl or aryl group having up to 20 carbon atoms in total. Also preferred are substituted alkyl groups having a total of up to 14 carbon atoms. This is an R1 group. A particularly preferred type of R1 group is a C, to C6 unsubstituted primary alkyl group. and C3 to C6 primary alkyl groups, with the terminal carbon atom being phenyl or alkyl. It is substituted with a kill-substituted phenyl. Examples of this preferred type include methyl 2-phenylethyl, ethyl, n-propyl, benzyl and 2-phenylethyl groups are included. .

Other particularly preferred types of R1 groups are 08-C4 unsubstituted secondary or tertiary alkyl groups and and C8 to C6 secondary or tertiary alkyl groups, packed into the remainder of the molecule. or the tertiary carbon atom is substituted with one or more phenyl groups. This species, Examples of the class include isopropyl, 5ec-butyl, tert-butyl, Ph (CH I) tC-Ph2(CL)C (in the formula, ph=phenyl), etc. Ru.

Considering that R is methyl, n-butyl, isobutyl and cyclopentyl compounds, available.

The single enantiomer of the chiral sultam identified above is as follows (wherein R and R1 the asymmetric water of the corresponding prochiral imine with Substantially optically pure forms can be prepared by elementary addition.

Accordingly, in one aspect of the invention, the following formula: (wherein and R1 are one or more chiral sultam enantiomers having an effective amount of ruthenium-containing asymmetric hydrogenation to prepare in optically pure form By reacting a brochiral imine of the following formula with hydrogen in the presence of a promoter: A method of preparation is provided.

Said specified method suitably involves a temperature range of 1 to 10 HPa at a temperature of 10 to 60°C. It is carried out in the liquid phase at a hydrogen pressure of . Suitable ruthenium-containing asymmetric hydrogenation catalysts is a complex consisting of ruthenium and a single enantiomer of chiral phosphine. Ru. In this connection, particularly suitable chiral phosphines are known in the art as BINAP 2,21-bis(diphenylphosphine-1,11-binaphthyl), known as ) and its ring-substituted derivatives.

Suitable catalyst precursors include RutC1,fBINAP)2N(C,Hs) ! , RuHCl-(BINAP)z, RIJ2 CI4 (11-TOIB INAP)2N(C2R5)s, and Ru2CI4(5-acetylamide (BINAP)2N(c2Hs)s, Ru(BINAP)(02CCHs) )2, etc., but independent sources of ruthenium and chiral phosphine It is also possible to generate a catalyst on the spot. These and other suitable species are It is described in more detail in EP245960.

Asymmetric hydrogenation is suitably carried out using an inert solvent such as dichloromethane, ethanol etc. or at the end of a reaction carried out in a mixture of solvents, a single molecule of chiral sultam. Nanthiomers are recovered by known techniques such as chromatography, recrystallization, etc.

In the case of chiral sultams in which the R1 group is secondary or tertiary alkyl, asymmetric hydrogenation Another method of addition is ++)-= in a dry solvent at a temperature in the range of -70 to -40°C. or the presence of (-)-N-methyl-efferidine and 3,5-dimethylphenol. A 10-chiral imine is brought into contact with lithium aluminum hydride.

When using this method, the products can be obtained in the usual manner.

The identified prochiral imine is saccharin or saccharin derivative of the following formula: It can be easily prepared by reacting a conductor with an alkylating agent. good Suitable alkylating agents have the formula (1) R'', M (where R' is as specified above). , M is a group IA, IIA or I[[A metal, and Z is the oxidation state of M. corresponding integer) or metal alkyl having the formula (2) R''　MgX (wherein , X is a halide). preferred alkyl Examples of the oxidizing agent include R'Li, R"HQCI, R'sAL, R's B etc. are included. 0, suitably under an inert dry atmosphere such as argon, nitrogen, etc. The process is carried out at temperatures below °C.

In addition to the methods described above, racemic incubation of chiral sultam enantiomers convert the mixture into a pair of corresponding diastereomers, followed by fractional crystallization It can be separated by a method consisting of: Diastereo easily separated The pair is a racemic mixture and one or more 10-camphorsulfumyl chloride enamers. It can be prepared by reacting with a thiomer.

The single enantiomer of the chiral sultam identified above has a range of brochiral sultams. It was determined that the ability to act as an effective chiral auxiliary agent for the reactants . In a method that takes advantage of this ability, a chiral sultam is converted into an appropriate prochiral sultam in the first step. reacts with natural precursors to form educts. The brochiral precursor used is reacts with the nitrogen atom of the normal sultam to convert the N-H bond into an N-Q bond (Q is prochiral). (a moiety derived from a precursor). prochiral A particularly useful class of precursors are the acyl halides of NiR2C0X, which are chiral reacts with a sultam to form an amide derivative according to the following general formula: In this formula, X is a halide and R2 is a carbon atom α for the carbonyl group. is a hydrocarbyl group that is reactive and prochiral in . play as desired The detached material can be separated from the used material on the spot.

The second step of this kind of process involves enolizing the educt and then using a suitable A chiral center is generated by reacting with an electronic agent. If you do this, the billing electronic agent will reacts selectively, and even if the reagent itself is not chiral, the new gives essentially only one of the two possible enantiomers of the product at the small chiral center. I can do it. I understand.

An example of the second step is the following formula: (In the formula, 2 is hydrogen or 01-C1゜alkyl, and R4 is C1-C1゜alkyl. is given by the reaction of the educt of erulate (which is a Ru. Therefore, the billing electronic agent R'　X, R'　COX, R'　CHOlRsCORs (wherein X is a halide and the R5 group is any one having 50 carbon atoms) (which is an organic group), hydrogen becomes -R', OCR', -CH (OH)R'l: gives the product substituted by -C(OH)RsRs Ru.

The product of the second step can be hydrolyzed with a base to cleave the N-C bond. , this regenerates the chiral sultam and converts the carboxylic acid corresponding to the nitrogen-bonded moiety into A single enantiomer of phosphoric acid is selectively produced.

The two steps involved in the above identified process involve the use of helocarbons or ethers The organic Obtain the desired material at each step using standard techniques in chemistry can be isolated.

The second example of the second step is the following general formula: (wherein R6 is C1-Cro alkyl) and C4-C1° Dialkyl malonate, C1-C8 alkyl ester of acetoacetic acid, cyano vinegar Non-pairing with enolizable compounds such as C1-C1° alkyl esters of acids, etc. It is given by the Michael reaction. In this type of reaction, the educt is It is characterized by being brochiral at the β carbon. This kind of Michael reaction is suitably in the presence of a base (e.g. secondary amine, alkali metal alkoxide, etc.) as in the first example, preferably carried out in a dry non-reactive solvent under an inert atmosphere. Once the Michael reaction occurs, the N-C bond is hydrolyzed and the corresponding carboxyl Can produce acid.

Another example of the second step is a cyclic conjugated diene and the following general formula: (wherein R7 is hydrogen or C1-C6 alkyl) It is given according to the response. Therefore, if the cyclic conjugated diene is cyclopentadiene , product: of the enantiomer (where chirality is induced at the marked carbon atom) The selectivity for one is high.As in the previous example, the above mentioned products can be hydrolyzed to form a chirality. Play a simple sultam with the following formula: A single enantiomer of a carboxylic acid can be produced.

Accordingly, in a further aspect of the invention, the following formula: (wherein the R groups are independently as defined above) R7 is hydrogen or C2-C1° alkyl, and R'' is -(CH 2) A single chiral carboxylic acid having the formula , - (wherein n is 1 to 6) In preparing enantiomers, (i) a single enantiomer of an educt having the formula: Reacting Oma with a cyclic conjugated diene of formula produces a single product having formula: (ii) the product is then hydrolyzed to form the enantiomers: A single enantiomer of a chiral sultam and a single enantiomer of a chiral carboxylic acid. A method of preparation is provided, which comprises liberating a polymer.

Step (i) of this method can be carried out under standard Diels-Alder conditions. can. Suitable catalysts for this process include aluminum, titanium, boron, etc. Lewis acids derived from tin and tin are included. The preferred catalyst is an alkyl aluminum compound, the most preferred being dimethylaluminum halide or diethylaluminum halide (halide is preferably C1 or B) ), step (11) suitably consists of base-catalyzed hydrolysis.

The invention will now be illustrated by the following examples.

艮1”Yu Brochiral imine from saccharide (R=H, R’=methystopr±y amount -benzoin sulfimide (saccharide) in THF (900 nl) at -78°C Methyllithium (30011) was added to a solution of (43.5 g, 240 mg mol) IM solution in EtzO, 475 mmol) was added. This solution was heated to -78°C. After stirring overnight, quench with saturated aqueous NH4C1 (4001) and evaporate with THF under vacuum. was removed. The aqueous suspension was extracted with EtOAC (3x600 ml) and saturated. Washed with aqueous NaCl solution (2001) and the combined extracts were dried (H(I) SO, ), removing the solvent gave a pink-white solid (38.2 g, yield = 88%), G C (150°C): 5.42 (imine, 100%) was obtained. For IH-NMR More impurities (5-10%) were detected.

This impurity was found to be the dimeric form of the methylated compound. During HeOH After recrystallization, white crystalline imine (33.56 g, 73%) in pure form, mp=218-219°C was isolated.

IR: 3030.　1565.　1460.　1380. 1345. 1 290. 1160. ” H-NMR: 2.65 (s, 3H), 7.7- 7.8 (Il, 3M), 7.85-7.95 (n.

1H), 13C-NMR: 17.55 (t), 122.33 (d), 12 4.07 (d).

131.413 (s), 133.80 (d), 133.93 (d), 13 9.49 (S).

173.17 (S), M S: 181 (Cm H? No□ S”, 50), 133 (45), 117 (55), 90 (30), 50 (90) , HR-M S: 181.0210 (C8H? NO2S”, calculated value = 1 81.0197>.

Cold JJLλ- Preparation of Put CI4 [(R)=(”)-BINAP]2 fNEti) L. 1, 21. Ka sweet [RuCl3 (cod)] placed in the sink tube of 2501, (3 8n+g, 0.13 mmol) and (R)-(-)-BINAP (90,2 dry degassed toluene under argon for a mixture of (3511> and dry degassed triethylamine (75ral, 0.54 mmol) ) was added. The resulting brown suspension was heated to reflux for 6 hours with stirring. Obtained The clear solution was cooled to room temperature and the solvent was removed under vacuum. Degassed commercial, The assembled product was extracted by CI□<3x2ml) and filtered under argon.

Removal of the solvent gave an orange crystalline product (>123 mg), which was purified with hydrogen. It was used as a catalyst in the addition step. The product was stored under argon.

11th day Chiral sultam (R=H, R'=methyl) from prochiral imine of Example 1 (R(+) of enantiomers: (R)-(+)-BINAP of Example 2 Catalyst (a!l+o+ig, 0.49 mmol) was added to CHi CI2 (10111 ) and then degassed ethanol (1000 nl) and dried under argon. The product of Example 1 (8,14 g, 4 4 mmol) into the reactor (21).

Hydrogenation was carried out at 22°C under 0.4 HPa of H2 for 12 hours. Solvent: a tM and remove the catalyst by flash chromatography on 5if2 to give a green color. Crystals (6.8 g, yield = 84%) were obtained.

After two recrystallizations in hexane/CH2Cl□, the enantiomerically pure sulfur Tam (5.8 g, yield = 72%) was obtained.

艮11: Example 2 (R)-(+)-BINAP X (692 ng, 0. 40 mmol) in CH2CI2 (5 nl) and then dried in argon. Examples in degassed ethanol (1001) and CH2Cl□ (5001) 1 (14 g, 77 mmol) into the reactor (21). 0.4 The solution was hydrogenated for 6 days at 22° C. under H2 in HPa. Concentrate the solvent The catalyst was removed by short flash 10 chromatography on SiOi. Ta. Enantiomerically pure by two recrystallizations in hexane/CH2C1□ Obtained sultam (9.15 g, 65%).

M P = 90.5-91.0 °C, mouth a] a = 27.7, ( c=1.15, CHCl3. 20℃), IR: 3360.304 0.2990.1455.1365.1323.1300°1170, 1160 ．． 1135. IH-NMR: 1.58 (d, J=7.3H).

4.74-4.90 (L 2H),? , 40 (d, J・7.5. IH ), 7.53 [t, J=7.5°IH), ? , 36 ftd, J.7 ．． 5.1.0.1H), 7.77 [d, J=8. IH).

13CNMR: 21.34 (t), 53.31 (d), 121.17 (d), 123.83 (d), 129.16 (d), 133.18 (d), 135.44 [s), 141.66 (s).

MS: 183 (Cm H, 802S"O), 168 (M"-CH ), 4).

150 (2), 120 (2,5), 107 (2,5), 83 (100) , HR-MS: 168.0121 (C7H6NO□S", calculated value = 168 ．． 0119).

Chestnut 10 box hill fs)(-)BniAp was used in Example 2 instead of the (R)(+) enantiomer. Examples 2 and 3 were repeated in the same manner, except that Therefore, the generated catalyst is Ru 2CL4 [(S)-(-)-BINAP:l 2 (NEi) s) , the corresponding 1s)(-) enantiomer of the chiral sultam is It was formed after hydrogenation of a normal imine.

Back 1st construction The product of Example 3 (1°9 g, 10.4 Add sodium hydride (680 mg, 15.6 mmol) to a solution of did. The mixture was stirred at 0° C. for 1 hour, then propionyl chloride (1.8 nl, 20 ．． 8 mmol) was added.

After the addition, the mixture was warmed to room temperature, stirred for an additional 16 h, and diluted with saturated aqueous NH4Cl. The solution was then added and the THF was distilled off under vacuum.

Extraction with CH2Cl2 was followed by distillation and chromatography (SiOi, hexane/ Crystallization from ethyl acetate (4:1) and methanol at 95°C, [α]. −19 , 5°C, Cm1.2 CHCl5').

Somdan N-(2S-2- M-3-phenyl (3R)-3-M-2,3-dihydro-1,2-ben Toning of diisothiazole-1,1-dioxide 1M solution of sodium hexamethyldisilazide (1.15ml) The product of Example 5 (250 mg, 1 mol) in THF (2 nl) at -78°C. ．． 045 mmol) over 30 minutes. This mixture was heated to -78°C. Stir for 30 minutes, add benzyl iodide (4ssmp, 2,09 mmol), Stir at -78°C for 2.5 hours, add saturated NH,CI aqueous solution, filter, and Et Stir with 20L, wash (H2O), dry the organic phase (NaCl), and distill. , Chromatography (SiOz, hexane/EtOAc 9:1) L, By crystallization (HeOH) the product (277nc+, 81%), m, p, A temperature of 73-75°C was obtained.

General procedure for preparing chiral sultam doacryloyl and tocrotonyl derivatives 1jlI A, acryloyl derivative Single chiral sultam with freshly distilled triethylamine in dichloromethane The mixture with enantiomers was cooled to 0° C. and acryloyl chloride was added. child Stir the solution for 1 hour at 0°C or at room temperature if the reaction is slow), and then The organic phase was separated and the aqueous solution was quenched with dichloromethane (equivalent volume of dichloromethane). The combined organics were extracted in 3x equal volumes of dichloromethane and dried (H gSO4) L, the solvent was removed to obtain the crude product, which was purified by FC and crystallization. and purified.

B. Ku! ” Third leg 1 presentation A solution of a single enantiomer of a chiral sultam in THF was prepared with hydrogen in THF at room temperature. was added dropwise to the suspension of sodium chloride and the solution was stirred for 1 hour. then tarot Nyl chloride was added dropwise and the mixture was stirred overnight, at the end of this time. , water and diethyl ether (equivalent volumes of THF). Upon rapid cooling, two layers were obtained, which were separated.

The aqueous phase was then further extracted using ether (equal volume of THF in 3 layers). The organic extract was dried and the solvent removed to obtain the crude product, which was subjected to FC and crystallization. It was purified by chemical reaction.

Hikitachi plate yu Chiral sultam (600u, 3.2 mmol) in CH2Cl□ (20 nl) ), triethylamine (389u, 3.85 mmol) and acryloylchloro Lido (348 IDg, 3.85 mmol) was added according to the procedure described in Method A above. After recrystallization from CH,C1□/hexane, R(-)-acryloyl derivative Conductor obtained (505119.2.13 mmol, 66%), H, I), 1 02-'C5 [α = 17.8', (c = 0.27. T = 20℃, C) 1 2CI2>.

Dango Hikitate S-sultan chiral sultam tocrotonyl: (leading to -, control (R=HR”=method) Le Using the method B single layer described above in THF (40111), the chiral sultam (1.0 g, 5.5 mmol), NaH (0.5 g of 55% suspension, 11.5 mmol) ) and tarotonyl chloride (0.57 g, 5.5 mmol), After recrystallization from tanol, S-(+) tarotonil derivative (0 , 82 g, 3.3 mmol, 60%). H, p, 135-136℃, [α] = Call 28.9, (C proverb 0.60. T-20°C, Et Kano).

N-Aroloyl Torotonyl: One element with diene - II Combine the sultam and excess diene in dichloromethane solvent and Cooled to temperature. A solution of Lewis acid was then added dropwise via a syringe. prescribed After the reaction time, add saturated ammonium chloride aqueous solution and dichloromethane (reaction solution to Prepare the reactants (unless otherwise specified) by adding 3 volumes each). ) Rapidly cooled to low temperature. After vigorous stirring, the layers were separated and further dichloromethane (5x The aqueous phase was extracted with 20 nl) and the combined organic extracts were dried with M (HgSO4). L, the solvent was removed to give the crude product, which was purified by FC.

-i about 1 more"-: This procedure was designed to reduce the degree of polymerization of the diene during the reaction. I measured it. Dissolve the sultam in dichloromethane and cool to a given temperature, at which point The appropriate amount of Lewis acid was added to the solution. After that, dichloromethane was added for 30 to 60 minutes. Add the diene dropwise in the form of a dilute solution in methane; after the complete addition, the reaction mixture is Stir for the stated time and then rapidly cool as described in the general procedure above. It was implemented according to the law.

1 plate of fish φ Preparation of Example 7 with cyclopentadiene carried out in dichloromethane (5 nl) The product of Example 7 (38011 (1,1,60 mmol) and cyclopentadiene (1 , 0 g, 15.1 mmol) and cooled to -98°C. HQ in 1 minute , dropwise addition of a solution of AICI (1, OH1; l, 3.21.3.2 mmol) did.

The reaction was complete after 10 min by TLC and was then quenched as described in the procedure. It was carried out. FC (gradient, elution started with 3:1 hexane:ethyl acetate) After recrystallization from dichloromethane/hexane) and dichloromethane/hexane, it appeared in the form of white crystals. The desired product was isolated (399ig, 1.32mmol, 83%), HPL C (hexane:ethyl acetate 95:5.21/min): Product after FC: 20.7 (0, 26, exo), 25.12 (1, 52, end), 25.81 (78, 73, end), thus 96% d, e, :r-’y do, after recrystallization: 27 ．． 55 (100, end), so 100% d, e, r, 7 de (standard dia Comparisons were made in each case using Stereo Eyes), H, 0, 16 7-169°C, [α] = -187,3 (c = 275. T = 20.1°C, above Following the procedure, the product of Example 9 (40 ng, 0.40 mmol) was dissolved in THF (2 , 5 ml) and LiOH (711 g, 0.27 mmol) in water (1 if). and hydrogen peroxide (88 μl of 30% solution, 27 μl H20□, 0.78 mmol 2 hours at 0°C. At the end of this time, 1.5 MNa2 The reaction was quenched using 1.1 equivalents of SOs. Remove THF under vacuum and dilute Sultam was extracted using chloromethane (2x51). Acidify the solution to pH 1 and extracted again using dichloromethane (5x 10Ill). The solvent was removed from the original sultam (13.1 rgg, 0.072 mmol, 5 5%). The solvent is removed from the second stage extract and a small amount of chiral sultam is A mixture of carboxylic acids was obtained (total amount of 17.6 rng: acid 14.7 mg, 0.11 mmol, 82%: Sultam, 2.911Q, 0.016 mmol, 12.2% ), a series of exhaustive acid/base extractions ensure that the carboxylic acids are completely free of sultam. It was possible to make it free from .

international search report IIImmmMIAalld111RMpCT/QiQ('110jlζ(-7

Claims (1)

[Claims] 1. The following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(l) (In the formula, R groups are independently hydrogen or C1 ~C6 alkyl, and the R1 group is C1-C20 alkyl or aryl substituted alkyl. a chiral sultam with a substantially optically pure form) A single enanteoma. 2. R1 is a C1-C6 unsubstituted primary alkyl group and a C1-C6 primary alkyl group (terminal carbon atom is substituted by phenyl or alkyl substituted phenyl) A single enantiomer of the chiral sultam of claim 1 selected from the group consisting of . 3. R1 is a C1-C6 unsubstituted secondary or tertiary alkyl group or a C1-C6 secondary or a tertiary alkyl group (one or more secondary or tertiary carbon atoms attached to the remainder of the molecule) of claim 1, which is substituted with a phenyl group of A single enantiomer of a chiral sultam. 4. R1 is other than methyl, n-butyl, isopropyl or cyclopropyl A single enantiomer or caries form of the compound having the general formula (I) according to claim 1, Lal Sultam. 5. The following general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R groups are independently hydrogen or C 1-C6 alkyl, and R1 is C1-C20 alkyl or aryl substituted alkyl. Q is -OCCH(Z)R4 and -OCC(Z)=CHR7 (in the formula , Z is hydrogen or C1-C10 alkyl, and R4 is C1-C10 alkyl. and R7 is hydrogen or C1-C6 alkyl) ru na sultam. 6. 6. The substituted chiral sultam of claim 5 in substantially optically pure form. A single enantiomer. 7. A single enantiomer of the chiral sultam having the general formula (I) according to claim 1 In preparing Oma, an effective amount of asymmetric hydrogenation catalyst is used according to the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼The corresponding prochiral imine of (III) Preparation of a single enantiomer of chiral sulcum by asymmetric hydrogenation. Manufacturing method. 8. The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R and R1 are as defined in claim 1. Z and R4 are as described in claim 5) Asymmetric electrophilic substitution at carbon atom α for carbonyl group in chiral sultams When carrying out (1) Single enantiomer of chiral sultam substituted using enolization reagent into enol, (2) Subsequently substituted chiral sulcum single enantiomer enolate and R 5X, RCOX, RCHO and R5COR5 (wherein R5 is independently any an electrophile selected from the group consisting of an organic group and X is a halide react with A method of performing asymmetric electrophilic substitution consisting of steps. 9. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and R1 are as described in claim 1, and Z is as described in claim 5. and R6 is C1-C10 alkyl) In the process, an asymmetric Michael addition is performed on the carbon-carbon double bonds α and β to the carbonyl group. When eating sea urchin, (1) C1-C10 dialkyl malonate, C1-C10 alkyl of acetoacetic acid selected from esters, C1-C10 alkyl esters of cyanoacetic acid and similar compounds. enolizing the selected enolizable compound; (2) A chiral sulk substituted with an enolate of a compound that can be subsequently enolized. react with a single enantiomer of A method of performing an asymmetric Michael addition consisting of steps. 10. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and R1 are as described in claim 1, and Z and R7 are as described in claim 5. A single enantiomer of a substituted chiral sultam with Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Cyclic conjugated diene (wherein R8 is -(CH2)■- and n is 1 to 8) An asymmetric Dales process consisting of a step of reacting with and optionally in the presence of a Lewis acid. ・Alder reaction.